N EW BO R N MET R IC C O N VER SIO N T ABLES
Temperature

FAHRENHEIT (F) TO CENTRIGRAD E (C)
°F

°C

°F

°C

°F

°C

°F

°C

95.0
95.2
95.4
95.6
95.8

35.0
35.1
35.2
35.3

35.4

98.0
98.2
98.4
98.6
98.8

36.7
36.8
36.9
37.0
37.1

101.0
101.2
101.4
101.6
101.8

38.3
38.4
38.6
38.7
38.8

104.0
104.2
104.4
104.6

104.8

40.0
40.1
40.2
40.3
40.4

96.0
96.2
96.4
96.6
96.8

35.6
35.7
35.8
35.9
36.0

99.0
99.2
99.4
99.6
99.8

37.2
37.3
37.4
37.6

37.7

102.0
102.2
102.4
102.6
102.8

38.9
39.0
39.1
39.2
39.3

105.0
105.2
105.4
105.6
105.8

40.6
40.7
40.8
40.9
41.0

97.0
97.2
97.4
97.6

97.8

36.1
36.2
36.3
36.4
36.6

100.0
100.2
100.4
100.6
100.8

37.8
37.9
38.0
38.1
38.2

103.0
103.2
103.4
103.6
103.8

39.4
39.6
39.7
39.8

39.9

106.0
106.2
106.4
106.6
106.8

41.1
41.2
41.3
41.4
41.6

NOTE: °C= (°F– 32) × 5/ 9. Centrigrade temperature equivalents rounded to one decimal place by adding 0.1 when second decimal place is 5 or greater.
The metric systemreplaces the term“centrigrade” with “Celsius” (the inventor of the scale).
See inside back cover for additional tables.


MEREN S TEIN & G A RDN ER’S HA N DBO O K O F

N eonatal Intensive Care
Ei g h t h Ed i ti o n

SAN DRA L. G ARDN ER, RN , MS, CN S, PN P
Director, Professional O utreach Consultation
Editor, N urse Currents and N ICU Currents
Aurora, Colorado

BRIAN S. CARTER, MD, FAAP

Professor of Pediatrics
University of Missouri-Kansas City School of Medicine
Division of Neonatology & Bioethics Center
Children’s Mercy Hospital-Kansas City
Kansas City, Missouri

MARY EN ZMAN HIN ES, Ph D, APRN , CN S, CPN P, APHN - BC
Professor Emeritus
Beth El College of Nursing and Health Sciences
University of Colorado at Colorado Springs;
Certified Pediatric Nurse Practitioner
R ocky Mountain Pediatrics
Lakewood, Colorado

JACIN TO A. HERN ÁN DEZ, MD, Ph D, MHA, FAAP
Professor Emeritus of Pediatrics
Section of Neonatology
Department of Pediatrics
University of Colorado School of Medicine;
Chairman Emeritus Department of Neonatology
Children’s Hospital Colorado
Aurora, Colorado


3251 R iverport Lane
St. Louis, Missouri 63043
MER ENSTEIN & GAR DNER ’S HANDBO O K OF NEO NATAL
INTENSIVE CAR E, EIGHTH EDITIO N

ISBN: 978-0-323-32083-2


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than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. In using such information or
methods they should be mindful of their own safety and the safety of others, including parties for whom they
have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most
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Library of Congress Cataloging-in-Publication D ata
Merenstein & Gardner’s handbook of neonatal intensive care / [edited by] Sandra L. Gardner, Brian S. Carter, Mary
Enzman Hines, Jacinto A. Hernandez. -- Eighth edition.
p. ; cm.
Merenstein and Gardner’s handbook of neonatal intensive care

Preceded by Merenstein & Gardner’s handbook of neonatal intensive care / [edited by] Sandra L. Gardner...
[et al.]. 7th ed. c2011.
Includes bibliographical references and index.
ISBN 978-0-323-32083-2 (pbk. : alk. paper)
I. Gardner, Sandra L., editor. II. Carter, Brian S., 1957- , editor. III. Hines, Mary Enzman, editor. IV. Hernandez,
Jacinto A., editor.V. Title Merenstein and Gardner’s handbook of neonatal intensive care.
[DNLM: 1. Intensive Care, Neonatal. 2. Infant, Newborn, Diseases--therapy. WS 421]
R J253.5
618.92’01--dc23
2015006347
Executive Content Strategist: Lee Henderson
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Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1


We dedicate this edition to the memory of Gerald B. Merenstein, MD—our friend,
colleague, and mentor who was also a wonderful husband, father, and grandfather. As the
inspiration for this text, Gerry contributed to the fields of neonatal and pediatric care
through his dedication to nurses, nurse practitioners, child health associates, interns, residents,
fellows, neonates, and their families. We miss him every day and know that his empathy,
knowledge, teaching, and compassion influences all of us, as well as the newborns, children,
and families that he and we serve.
SLG

BSC


MEH

JAH

In memory of Stephanie Marie Gardner, whose three days of life did have a purpose.
SLG

To my family: Angel, Sean,Yvonne, R ebecca, and Jacquelyn; my mentors and colleagues; and
all of the children and families who have allowed me to share with them both joyous and
difficult times in their lives.
BSC

To my family James, Jennifer, Sean, Finnoula, Steve, and Sarah for their enduring source of
love, confidence, and encouragement and to all the families who have informed by practice
and knowledge about caring for fragile infants.
MEH

To all the newborn infants, their families, and dedicated caregivers; my beloved wife Pam
and sons Gabriel and Jacinto for their love and constant support.
JAH

In Memoriam
Jimmie Lynne Scholl Avery
L. Joseph Butterfield, MD
Lula O. Lubchenco, MD
William A. Silverman, MD


C O N T R IBU T O R S


Rta Agarwal, MD, FAAP

La ra D. Brown, MD

Professor of Anesthesiology
Director of Education, Pediatric Anesthesia
Pediatric Anesthesia Program Director
Director of the Colorado R eview of Anesthesiology for
Surgicenters and Hospital
Children’s Hospital Colorado, University of Colorado
Denver, School of Medicine
Aurora, Colorado

Associate Professor of Pediatrics
Section of Neonatology
Department of Pediatrics
University of Colorado Denver School of Medicine
Aurora, Colorado

Mar anne Sollosy Anderson, MD
Neonatologist
Sequoia Pediatrics
Kaweah Delta Medical Center
Visalia, California

Ja me Arr da, MD, FACOG
Assistant Professor, O bstetrics and Gynecology
University of Colorado Denver
Aurora, Colorado


James S. Barry, MD
Associate Professor of Pediatrics, Section of Neonatology
Department of Pediatrics
University of Colorado Denver School of Medicine
Medical Director, Neonatal Intensive Care Unit
University of Colorado Hospital Department of
Neonatology Children’s Hospital Colorado
Aurora, Colorado

Wanda Todd Bradshaw, MSN, RN, NNP-BC
Assistant Professor and Lead Faculty, NNP Specialty
Duke University School of Nursing
Durham, North Carolina;
Neonatal Nurse Practitioner
Moses Cone Health System
Greensboro, North Carolina

M. Colleen Brand, PhD, APRN, NNP-BC
Neonatal Nurse Practitioner
Texas Children’s Hospital
Houston, Texas

iv

Jess ca Br nkhorst, MD
Neonatology Fellow
Children’s Mercy Hospital
Kansas City, Missouri


Br an T. B cher, MD
Clinical Fellow
Pediatric Surgery
Department of Pediatric Surgery
Vanderbilt
Nashville, Tennessee

Deanne B schbach, RN, MSN, NNP, PNP
Clinical O perations Director for Advanced Clinical
Practice
Pediatric and Neonatal Critical Care APP Service
Pediatric Heart APP Service
Duke University Medical Center
Durham, North Carolina

Mel ssa A. Cadnapaphorncha , MD
Associate Professor of Pediatrics and Medicine
Pediatric Nephrology/ The Kidney Center
University of Colorado Denver School of Medicine and
Children’s Hospital Colorado
Aurora, Colorado

Angel Carter, DNP, APRN, NNP-BC
Assistant Professor of Nursing
Assistant Chair—BSN Degree Completion Program
Park University
Kansas City, Missouri


CONTRiBuTORS


Br an S. Carter, MD, FAAP

Nancy Engl sh, PhD, RN

Professor of Pediatrics
University of Missouri-Kansas City School of Medicine
Division of Neonatology & Bioethics Center
Children’s Mercy Hospital-Kansas City
Kansas City, Missouri

Fetal Concerns, Director and Coordinator
Colorado High R isk Maternity and Newborn Program
University of Colorado Health Sciences
The Children’s Hospital
Aurora, Colorado

S san B. Clarke, MS, RNC-NiC, RN-BC, CNS

Mary Enzman Hnes, PhD, APRN, CNS, CPNP, APHN-BC

Professional Development Specialist
Continuing Education and O utreach
NR P R egional Trainer
Children’s Hospital Colorado
Aurora, Colorado

Professor Emeritus
Beth El College of Nursing and Health Sciences
University of Colorado at Colorado Springs;

Certified Pediatric Nurse Practitioner
R ocky Mountain Pediatrics
Lakewood, Colorado

C. Mchael Cotten, MD, MHS
Associate Professor of Pediatrics
Medical Director, Neonatology Clinical R esearch
Duke University
Durham, North Carolina

Heather F rlong Craven, MD
Associate Professor of Pediatrics
Division of Neonatology
Medical Director of Neonatal Transport Services
Wake Forest School of Medicine Brenner Children’s
Hospital
Winston-Salem, North Carolina

v

Lor Er ckson, RN, CPNP, APRN
Fetal Cardiac and Cardiac High Acuity
Monitoring APR N
Ward Family Heart Center
Children’s Mercy Hospital
Kansas City, Missouri

R th Evans, MS, APRN, NNP-BC
Neonatal Nurse Practitioner
Children’s Hospital Colorado and University of

Colorado Hospital
Aurora, Colorado

Jane Dav s, RNC, BSN

Loretta P. Fnnegan, MD

Level III Permanent Charge Nurse
Neonatal Intensive Care Unit
University of Colorado Hospital
Aurora, Colorado

President, Finnegan Consulting, LLC
Perinatal Addiction and Women’s Health
Avalon, New Jersey;
Founder and Former Director of Family Center
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania

Jane Deacon, NNP-BC, MS
Neonatal Nurse Practitioner
Children’s Hospital Colorado
Aurora, Colorado

Dav d J. D rand, MD
Division of Neonatology
UCSF Benioff Children’s Hospital-O akland
O akland, California

Jarrod D s n, MS, RD

Clinical Dietitian Specialist
Children’s Mercy Hospital
Kansas City, Missouri

Sandra L. Gardner, RN, MS, CNS, PNP
Director, Professional O utreach Consultation
Editor, N urse Currents and N ICU Currents
Aurora, Colorado

Edward Goldson, MD
Professor, Department of Pediatrics
University of Colorado Denver School of Medicine
The Children’s Hospital
Aurora, Colorado


vi

CONTRiBuTORS

Lnda L. Gratny, MD

Mona Jacobson, MSN, RN, CPNP-PC

Associate Professor of Pediatrics
University of Missouri-Kansas City School of Medicine;
Neonatologist and Director, Infant Tracheostomy and
Home Ventilator Program
Children’s Mercy Hospital
Kansas City, Missouri


Instructor in Pediatrics
Section of Child Neurology
University of Colorado School of Medicine
Children’s Hospital Colorado
Aurora, Colorado

Mar e Hast ngs-Tolsma, PhD, CNM, FACNM

Senior Associate Dean for Clinical Affairs
Professor, Section of Neonatology
Department of Pediatrics
University of Colorado Denver School of Medicine
Aurora, Colorado

Professor, Nurse Midwifery
Louis Herrington School of Nursing
Baylor University
Dallas, Texas;
Visiting Professor
University of Johannesburg
Johannesburg, South Africa

Wll amW. Hay Jr., MD
Professor of Pediatrics, Section of Neonatology
Scientific Director, Perinatal R esearch Center
Co-Director for Child and Maternal Health and the
Perinatal R esearch Center, Colorado Clinical and
Translational Sciences Institute
University of Colorado School of Medicine and

Children’s Hospital Colorado
Aurora, Colorado

Kendra Hendr ckson, MS, RD, CNSC, CSP
Clinical Dietitian Specialist
Neonatal Intensive Care Unit
University of Colorado Hospital
Aurora, Colorado

Carmen Hernández, MSN, NNP-BC
Neonatal Nurse Practitioner
R ocky Mountain Hospital for Children
Denver, Colorado

Jacnto A. Hernández, MD, PhD, MHA, FAAP
Professor Emeritus of Pediatrics
Section of Neonatology
Department of Pediatrics
University of Colorado School of Medicine;
Chairman Emeritus Department of Neonatology
Children’s Hospital Colorado
Aurora, Colorado

Patt Hlls, LMSW, LCSW
Fetal Health Center
NICU Social Worker
Children’s Mercy Hospital
Kansas City, Missouri

M. Do glas Jones, Jr., MD


Beena Kamath-Rayne, MD, MPH
Assistant Professor of Pediatrics
Perinatal Institute, Division of Neonatology
Global Health Center
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio

Rhonda Knapp-Clevenger, PhD, CPNP
Director, R esearch and Pediatric Nurse Scientist
Center for Pediatric Nurse R esearch and Clinical Inquiry;
Clinical R esearch Director, Pediatric and Perinatal
Clinical Translational R esearch Centers
University of Colorado Denver, College of Nursing
Children’s Hospital Colorado
Aurora, Colorado

R th A. Lawrence, MD, DD(Hon), FAAP, FABM
Distinguished Alumna Professor of Pediatrics and
O bstetrics/ Gynecology
Northumberland Trust Chair in Pediatrics
Director of the Breastfeeding and Human Lactation
Study Center
University of R ochester School of Medicine and Dentistry
R ochester, New York

Mary Kay Le ck-R de, RNC, MSN, PCNS
Clinical Nurse Specialist
Children’s Mercy Hospital
Kansas City, Missouri


Harold Lovvorn iii, MD, FACS, FAAP
Assistant Professor of Pediatric Surgery
Vanderbilt University Children’s Hospital
Nashville, Tennessee


CONTRiBuTORS

Carolyn L nd, RN, MS, FAAN

Pr sclla M. Nod ne, PhD, CNM

Neonatal Clinical Nurse Specialist
ECMO Coordinator
Neonatal Intensive Care Unit
UCSF Benioff Children’s Hospital-O akland
O akland, California;
Associate Clinical Professor
Department of Family Health Care Nursing
University of California
San Francisco, California

Assistant Professor, Midwifery
College of Nursing
University of Colorado Anschutz Campus
Aurora, Colorado

Mar lyn Manco-Johnson, MD
Professor of Pediatrics, Section of Hematology

University of Colorado Denver and The Children’s
Hospital Colorado
Hemophilia and Thrombosis Center
Aurora, Colorado

Anne Matthews, RN, PhD, FACMG
Professor
Genetics and Genome Sciences
Director, Genetic Counseling Training Program
Case Western R eserve University
Cleveland, O hio

vii

Mchael Nyp, DO, MBA
Assistant Professor of Pediatrics
University of Missouri-Kansas City
Division of Perinatal-Neonatal Medicine
Children’s Mercy Hospital
Kansas City, Missouri

Steven L. Olsen, MD
Associate Professor of Pediatrics
University of Missouri-Kansas City
Division of Neonatology
Children’s Mercy Hospital
Kansas City, Missouri

Annette S. Pacett , RN, MSN, NNP-BC
Neonatal Nurse Practitioner

Monroe Carell, Jr. Children’s Hospital at Vanderbilt
Nashville, Tennessee

Jane E. McGowan, MD

E gen a K. Pallotto, MD, MSCE

Professor of Pediatrics
Associate Chair for R esearch
Drexel University College of Medicine
Medical Director, NICU
St. Christopher’s Hospital for Children
Philadelphia, Pennsylvania

Associate Professor
University of Missouri-Kansas City School of Medicine
Medical Director, NICU
Children’s Mercy Hospital
Kansas City, Missouri

Chr stopher McKnney, MD

Associate Professor
Baylor College of Medicine
Houston, Texas

Fellow, Pediatric Hematology
Center for Cancer and Blood Disorders
Children’s Hospital Colorado
University of Colorado-Denver

Aurora, Colorado

Mary Mller-Bell, PharmD
Clinical R esearch Pharmacist
Duke University Hospital
Durham, North Carolina

S san Nermeyer, MD, MPH, FAAP
Professor of Pediatrics and Epidemiology
University of Colorado School of Medicine and
Colorado School of Public Health
Aurora, Colorado

Mohan Pamm, MD, PhD, MRCPCH

Alfonso Pantoja, MD
Neonatologist
Saint Joseph’s Hospital
Denver Colorado

J l e A. Parsons, MD
Associate Professor of Pediatrics and Neurology
Haberfield Family Endowed Chair in Pediatric
Neuromuscular Disorders
Child Neurology Program Director
University of Colorado School of Medicine
Children’s Hospital Colorado
Aurora, Colorado



viii

CONTRiBuTORS

Webra Pr ce-Do glas, PhD, CRNP, iBCLC

Dan elle E. Soranno, MD

Maryland R egional Transport Program
Baltimore, Maryland

Assistant Professor of Pediatrics and Bioengineering
Pediatric Nephrology/ The Kidney Center
University of Colorado Denver School of Medicine and
Children’s Hospital Colorado
Aurora, Colorado

Daphne A. Reavey, PhD, RN, NNP-BC
Neonatal Nurse Practitioner
Children’s Mercy Hospital
Kansas City, Missouri

Nathan el H. Rob n, MD, FACMG
Professor of Genetics and Pediatrics
University of Alabama at Birmingham
Birmingham, Alabama

Mar o A. Rojas, MD, MPH
Professor of Pediatrics
Division of Neonatal-Perinatal Medicine

Wake Forest University School of Medicine
Winston Salem, North Carolina

Jame Rosterman, DO
Neonatology Fellow
Children’s Mercy Hospital
Kansas City, Missouri

Pa l Rozance, MD
Associate Professor of Pediatrics
Section of Neonatology
University of Colorado Denver School of Medicine
Children’s Hospital Colorado
Aurora, Colorado

Tamara R sh, MSN, RN, C-NPT, EMT
Nurse Manager
Brenner Children’s Hospital-Wake Forest Baptist Health
Winston-Salem, North Carolina

Mary Schoenbe n, BSN, RN, CNN
Perinatal Dialysis Nurse/ The Kidney Center
Children’s Hospital Colorado
Aurora, Colorado

Alan R. Seay, MD
Professor of Pediatrics and Neurology
University of Colorado School of Medicine
Children’s Hospital Colorado
Aurora, Colorado


John Stra n, MD, FACR, CAQPedatr cRadology, Ne roradology
Professor of R adiology
Department of R adiology
University of Colorado School of Medicine;
Chairman, Department of R adiology
Children’s Hospital Colorado
Anschutz Medical Campus
Aurora, Colorado

J l e R. Swaney, MDv
Manager, Spiritual Care Services
Associate Clinical Professor, Department of Medicine
University of Colorado Denver Anschutz Medical Campus
Aurora, Colorado

Tara M. Swanson, MD
Assistant Professor of Pediatrics
University of Missouri-Kansas City School of Medicine;
Director of Fetal Cardiology
Children’s Mercy Hospital
Kansas City, Missouri

Dav d Tanaka, MD
Professor of Pediatrics
Neonatologist
Duke University Medical Center
Durham, North Carolina

El zabeth H. Th lo, MD

Associate Professor of Pediatrics
Section of Neonatology
University of Colorado Denver School of Medicine;
Neonatologist
University of Colorado Hospital and Children’s Hospital
Colorado
Aurora, Colorado

Kr st n C. Voos, MD
Neonatologist
Children’s Mercy Hospital;
Associate Professor of Pediatrics
University of Missouri-Kansas City School of Medicine
Kansas City, Missouri


CONTRiBuTORS

S san M. We ner, PhD, MSN, RNC-OB, CNS

Leonard E. We sman, MD

Perinatal Clinical Nurse Specialist
Assistant Clinical Professor/ R etired
Freelance Author/ Editor
Philadelphia, Pennsylvania

Professor of Pediatrics
Section of Neonatology
Baylor College of Medicine

Texas Children’s Hospital
Houston, Texas

Jason P. We nman, MD
Assistant Professor of R adiology
University of Colorado School of Medicine
Medical Director Computed Tomography
Children’s Hospital Colorado
Aurora, Colorado

Rosanne J. Wolosch k, RD
Clinical Dietitian
The Kidney Center
Children’s Hospital Colorado
Aurora, Colorado

ix


R EVIEW ER S

Nancy Blake, PhD, RN, NEA-BC, CCRN

Nadine A. Kassity-Krich, MBA, BSN, RN

Patient Care Services Director
Critical Care Services
Children’s Hospital Los Angeles
Los Angeles, California


Clinical Professor
Hahn School of Nursing
University of San Diego
San Diego, California

Fran Blayney, RN-C, BSN, MS, CCRN

Lisa M. Kohr, RN, MSN, CPNP- AC/ PC, MPH, PhD(c), FCCM

Education Manager
Pediatric Intensive Care Unit
Children’s Hospital Los Angeles
Los Angeles, California

Pediatric Nurse Practitioner
Cardiac Intensive Care Unit
Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania

Karen C. D’Apolito, PhD, NNP-BC, FAAN

Carie Linder, RNC-NIC, MSN, APRN-BS

Professor & Program Director
Neonatal Nurse Practitioner Program
Vanderbilt University School of Nursing
Nashville, Tennessee

Neonatal Nurse Practitioner
Integris Baptist Medical Center

O klahoma City, O klahoma

Mary Dix, BSN, RNC-NIC

Pediatric Pain Service
Monroe Carell Jr. Children’s Hospital at Vanderbilt
Nashville, Tennessee

Staff Nurse
Neonatal Intensive Care Unit
PIH Health Hospital-Whittier
Whittier, California

Sharon Fichera, RN, MSN, CNS, NNP-BC
Neonatal Clinical Nurse Specialist
Children’s Hospital Los Angeles
Los Angeles, California

Joyce Foresman-Capuzzi, MSN, RN
Clinical Nurse Educator
Lankenau Medical Center
Wynnewood, PA

Delores Green ood, MSN, RNC-NIC
Education Manager, Newborn and Infant Critical
Care Unit
Children’s Hospital Los Angeles
Los Angeles, California

x


T ila Luckett, BSN, RN-BC

Erin L. Marriott, MS, RN, CPNP
Pediatric Cardiology Nurse Practitioner
American Family Children’s Hospital
Watertown R egional Medical Center
Madison, Wisconsin

Andrea C. Morris, DNP, RNC-NIC, CCRN
Neonatal Clinical Nurse Specialist
CitrusValley Medical Center-NICU
West Covina, California

Mindy Morris, DNP, NNP-BC, CNS
Neonatal Nurse Practitioner
Extremely Low Birth Weight Program Coordinator
Children’s Hospital of O range County
O range, California


REvIEwERS

Tracy Ann Pasek, RN, MSN, DNP, CCNS, CCRN, CIMI

Nicole van Hoey, PharmD

Clinical Nurse Specialist
Pain/ Pediatric Intensive Care Unit
Children’s Hospital of Pittsburgh

University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania

Medical Writer/ Editor
Consultant
Arlington,Virginia

Patricia Scheans, DNP, NNP-BC
Clinical Support for Neonatal Care
Legacy Health
Portland, O regon

Peggy Slota, DNP, RN, FAAN
Associate Professor
Director, DNP and Nursing Leadership Programs
Carlow University
Pittsburgh, Pennsylvania

winnie Yung, MN, RN
R egistered Nurse
Lucile Packard Children’s Hospital at Stanford
Palo Alto, California

xi


PR EFAC E

T


he concept of the team approach is important in neonatal intensive care. Each health
care professional must not only perform the
duties of his or her own role but must also understand
the roles of other involved professionals. Nurses,
physicians, other health care providers, and parents
must work together in a coordinated and efficient
manner to achieve optimal results for patients in the
neonatal intensive care unit (NICU).
Because this team approach is so important in
the field of neonatal intensive care, we believe it is
necessary that this book contain input from major
fields of health care—nursing and medicine. Both
nurses and physicians have edited and co-authored
every chapter.
The book is divided into six units, all of which
have been reviewed, revised, and updated for the
eighth edition. Unit One presents evidence-based
practice and the need to scientifically evaluate neonatal therapies, emphasizing randomized controlled
trials as the ideal approach. Units Two through Five
are the clinical sections, which have been fully
updated for this edition. The chapters within these

xii

sections include highlighted clinical directions for
quick reference, Parent Teaching boxes to aid in discharge instructions, and Critical Findings boxes to
prioritize assessment data.
The combination of physiology and pathophysiology and separate emphasis on clinical application
in this text is designed for neonatal intensive care
nurses, nursing students, medical students, and pediatric, surgical, and family practice housestaff. This

text is comprehensive enough for nurses and physicians, yet basic enough to be useful to families and
all ancillary personnel.
Unit Six presents the psychosocial aspects of
neonatal care. The medical, psychological, and social
aspects of providing care for the ill neonate and family are discussed in this section.This section in particular will benefit social workers and clergy, who often
deal with family members of neonates in the NICU.
In this handbook we present physiologic principles and practical applications and point out areas as
yet unresolved. Material that is clinically applicable is set in purple type so that it can be
easily identified.


IN T R O D U C T IO N

I

n 1974 as the Perinatal O utreach Educator at
The Children’s Hospital in Denver, Colorado,
I took a folder to Gerry Merenstein, MD, at
Fitzsimmons Army Medical Center to discuss his
lectures for the first outreach education program in
La Junta, Colorado. When we finished, he removed
from his desk drawer a 1-inch thick compilation of
the neonatal data, graphs, nomograms, and diagrams
he had created for the medical housestaff during his
fellowship. Giving the document to me, he asked
that I review it and let him know what I thought.
Several weeks later, I told him it was good except
there was no nursing care or input, which is essential
in every NICU. So Gerry asked, “Want to write a
book?”—and the idea for the Handbook was born!

With this eighth edition in 2015, we celebrate 30
years of publication of the Handbook of Neonatal Intensive
Care. Gerry and I co-edited this book for 21 years until
his death in December 2007.To fulfill my promise that
Gerry’s name would always be on the book, the seventh
and all subsequent editions will be known as Merenstein & Gardner’s Handbook of Neonatal Intensive Care.
Instead of editing this edition alone or with another
physician, I decided to convene an editorial team consisting of myself, a nurse colleague, and two neonatologists. Together we bring 170 years of clinical practice,
research, teaching, writing, and consulting in neonatal,
pediatric, and family care to this eighth edition.
We have the distinction in this new edition of translation into Spanish for our colleagues in Central and
South America and Spain. This was an ongoing wish
of Gerry Merenstein, and after much negotiation it
is finally a reality. Welcome to all our Spanish-reading
colleagues! In addition, the eighth edition is available
on multiple e-platforms to facilitate use at the bedside.
For our new audience, and for our continuing
loyal readers, this is my opportunity to introduce
myself and all the members of the editing team.
I am currently Editor of Nurse Currents and NICU
Currents (www.anhi.org) and the Director of Professional Outreach Consultation (www.professionaloutreachconsultation.com), a national and international

consulting firm established in 1980. I plan, develop,
teach, and coordinate educational workshops on
perinatal/ neonatal/ pediatric topics. I graduated from
a hospital school of nursing in 1967 with a diploma,
obtained my BSN at Spalding College in 1973 (magna
cum laude), completed my MS at The University of
Colorado School of Nursing in 1975 and my PNP
in 1978. I have worked in perinatal/ neonatal/ pediatric

care since 1967 as a clinician (37 years in direct bedside
care), practitioner, teacher, author, and consultant. In
1974, I was the first Perinatal Outreach Educator in the
United States funded by the March of Dimes. In this
role I taught nurses and physicians in Colorado and the
seven surrounding states how to recognize and stabilize
at-risk pregnancies and sick neonates. I also consulted
with numerous March of Dimes grantees to help them
establish perinatal outreach programs. In 1978 I was
awarded the Gerald Hencmann Award from the March
of Dimes for “outstanding service in the improvement
of care to mothers and babies in Colorado.” I am a
founding member of the Colorado Perinatal Care
Council, a state advisory council to the Governor and
the State Health Department on perinatal/ neonatal
health care issues, and I am the Treasurer and a member
of the Executive Committee. I am also an active member of the Colorado Nurses Association/ American
Nurses Association, the Academy of Neonatal Nurses,
and the National Association of Neonatal Nurses.
Mary Enzman Hines, R N, PhD, CNS, CPNP,
AHN-BC, is currently Professor Emeritus at Beth-El
College of Nursing at the University of Colorado in
Colorado Springs and certified Pediatric Nurse Practitioner at R ocky Mountain Pediatrics, Lakewood,
Colorado. Early in her nursing career, Mary worked
in the NICU and PICU as a staff nurse, charge nurse,
and nurse manager. After completing her PNP/ CNS
program and her master’s degree at the University of
Colorado, Mary became the Neonatal and Pediatric
Clinical Nurse Specialist at Denver Health and Hospital, where she created a beginning, intermediate, and
advanced orientation for nurses in the NICU and

PICU. At the University of Colorado, Mary accepted

xiii


xiv

Int r oduct Ion

the practitioner/ teacher role in maternal-child services,
providing clinical care and mentorship in the NICU
and pediatric units where nursing students were placed
from the CU nursing program. When University
Hospital and The Children’s Hospital combined their
pediatric services, Mary became the Clinical Nurse
Specialist in R esearch and Education and consulted in
the NICU, PICU, and pediatric medical-surgical areas.
In this role she was a founding member of the interdisciplinary Pain Management Team and provided consultation throughout The Children’s Hospital for pain
management issues. In 1996 Mary became a nursing
faculty member at Beth-El College of Nursing and
Health Sciences, where she created a student health
center at the University and a school-based clinic for
schoolchildren in Fountain, Colorado, while maintaining an active pediatric practice at Colorado Springs
Health Partners. Currently Mary provides pediatric
care at R ocky Mountain Pediatrics and continues to
teach courses to DNP students at the University of
Northern Colorado as an adjunct faculty. Mary is well
published in the areas of pediatric, neonatal, and family
health care, as well as in legal issues in maternal-child
nursing. Mary is also a nurse researcher in the areas

of pain, chronic illness, caring/ healing praxis, pediatric
pain, holistic nursing, and technology in health care.
Brian S. Carter, MD, FAAP, is a graduate of David
Lipscomb College in Nashville, Tennessee, and of
the University of Tennessee’s College of Medicine in
Memphis, Tennessee. Brian completed his residency
in pediatrics at Fitzsimmons Army Medical Center
in Aurora, Colorado. He completed his fellowship
in neonatal-perinatal medicine at the University of
Colorado Health Sciences Center in Denver. During
the “Baby Doe” era, Brian trained in bioethics and, in
addition to clinical neonatology and neonatal followup, he has dedicated most of his academic career to
the advancement of clinical ethics in neonatology and
pediatric palliative care. Brian has been recognized
nationally for his efforts in both of these fields. Currently he is Professor of Pediatrics at the University
of Missouri-Kansas City School of Medicine, where
he serves on the Ethics Committee and mentors students, residents, and fellows in the areas of clinical ethics, neonatology, pain management, and palliative care.
Brian, Marcia Levetown, MD, and Sarah Friebert, MD,
co-edit the book Palliative Care for Infants, Children, and
Adolescents:A Practical Handbook, whose second edition
published in 2011 by Johns Hopkins University Press.
Jacinto A. Hernández, MD, PhD, MHA, FAAP, is
currently Professor Emeritus of Pediatrics and Neonatology at the University of Colorado Denver and

Chairman Emeritus of the Department of Neonatology at Children’s Hospital Colorado, Aurora Colorado. He is a graduate of the School of Medicine of
the University of San Marcos in Lima, Peru. Jacinto’s
postgraduate education includes a specialty in pediatrics
and a subspecialty in neonatology from the Children’s
Hospital National Medical Center and George Washington University in Washington, DC, and from the
University of Colorado Denver School of Medicine; a

PhD from the University of San Marcos; and a Master’s
in Health Administration from the University of Colorado Denver School of Business. Jacinto has spent all of
his professional life in academic medicine, first at the
University of San Marcos asAssociate Professor of Pediatrics, and subsequently at the University of Colorado
Denver School of Medicine as Professor of Pediatrics.
As a physician and professor, his professional activities
have been carried out at The Children’s Hospital of
Denver in Aurora, Colorado, where he has been Director of the Newborn Intensive Care Unit, Chairman of
the Department of Neonatology, an active staff neonatologist, and President of the Medical Staff. During his
career, Jacinto has distinguished himself both clinically
and academically, has written numerous publications in
the field of neonatal medicine, and has participated as
an invited professor at innumerable international events.
Jacinto has been recognized with numerous awards,
including the Career Teaching and Scholar Award, for
his scientific achievements, professional qualities, and
fruitful work as a superb clinical physician.
Borrowing from the words of Brian Carter in the
introduction to the sixth edition of the Handbook:
The goals of care should be patient- and familycentered. It is the patient we treat, but it is the family,
of whatever construct, with whom the baby will go
home. Indeed, it is the family who must live with the
long-term consequences of our daily decisions in caring
for their baby.
These goals include the provision of skilled professional care. An effective neonatal intensive care
team consists of educated professionals of many
disciplines—none of us can do it alone.
It has been my honor and privilege to work with
these co-editors, who are all patient- and familycentered, and with the amazing editing team of Tina
Kaemmerer, Lee Henderson, and Carol O ’Connell

for this eighth edition.
Sandra L. Gardner RN, MS, CN S, PN P
Senior Editor


C O N T EN T S

UNIT ONE

Evidence-Based Practice
1.

Evidence-Based Clinical Practice, 1
Alfonso F. Pantoja and Mary Enzman Hines

UNIT TWO

Support of the Neonate
2.

Prenatal Environment: Effect on Neonatal
Outcome, 11
Priscilla M. Nodine, Marie Hastings-Tolsma, and Jaime Arruda

3.

Perinatal Transport and Levels of Care, 32
Mario Augusto Rojas, Heather Furlong Craven, and Tamara Rush

4.


Delivery R oom Care, 47

11. Drug Withdrawal in the Neonate, 199
Susan M. Weiner and Loretta P. Finnegan

12. Pain and Pain R elief, 218
Sandra L. Gardner, Mary Enzman Hines, and Rita Agarwal

13. The Neonate and the Environment: Impact
on Development, 262

Sandra L. Gardner, Edward Goldson, and Jacinto A. Hernández

UNIT THREE

Metabolic and Nutritional
Care of the Neonate
14. Fluid and Electrolyte Management, 315
Michael Nyp, Jessica L. Brunkhorst, Daphne Reavey, and
Eugenia K. Pallotto

Susan Niermeyer, Susan B. Clarke, and Jacinto A. Hernández

5.

Initial Nursery Care, 71
Sandra L. Gardner and Jacinto A. Hernández

6.


Heat Balance, 105
Sandra L. Gardner and Jacinto A. Hernández

7.

Physiologic Monitoring, 126
Wanda Todd Bradshawand David T. Tanaka

8.

Acid-Base Homeostasis and
Oxygenation, 145
James S. Barry, Jane Deacon, Carmen Hernández, and
M. Douglas Jones, Jr.

9.

Diagnostic Imaging in the Neonate, 158
John D. Strain and Jason P. Weinman

10. Pharmacology in Neonatal Care, 181

15. Glucose Homeostasis, 337
Paul J. Rozance, Jane E. McGowan, Webra Price-Douglas, and
William W. Hay, Jr.

16. Total Parenteral Nutrition, 360
Steven L. Olsen, Mary Kay Leick-Rude, Jarrod Dusin, and
Jamie Rosterman


17. Enteral Nutrition, 377
Laura D. Brown, Kendra Hendrickson, Ruth Evans, Jane Davis,
Marianne Sollosy Anderson, and William W. Hay, Jr.

18. Breastfeeding the Neonate with Special
Needs, 419

Sandra L. Gardner and Ruth A. Lawrence

19. Skin and Skin Care, 464
Carolyn Lund and David J. Durand

Mary Miller-Bell, Charles Michael Cotten, and Deanne Buschbach

xv


xvi

CONTENTS

UNIT FOUR

Infection and Hematologic Diseases
of the Neonate
20. Newborn Hematology, 479
Marilyn Manco-Johnson, Christopher McKinney, Rhonda
Knapp-Clevenger, and Jacinto A. Hernández


21. Neonatal Hyperbilirubinemia, 511
Beena D. Kamath-Rayne, Elizabeth H. Thilo, Jane Deacon, and
Jacinto A. Hernández

22. Infection in the Neonate, 537
Mohan Pammi, M. Colleen Brand, and Leonard E. Weisman

UNIT FIVE

Common Systemic D iseases of the
Neonate
23. R espiratory Diseases, 565
Sandra L. Gardner, Mary Enzman Hines, and Michael Nyp

24. Cardiovascular Diseases and Surgical
Interventions, 644
Tara Swanson and Lori Erickson

25. Neonatal Nephrology, 689
Melissa A. Cadnapaphornchai, Mary Birkel Schoenbein, Rosanne
Woloschuk, Danielle E. Soranno, and Jacinto A. Hernández

26. Neurologic Disorders, 727
Julie A. Parsons, Alan R. Seay, and Mona Jacobson

27. Genetic Disorders, Malformations, and
Inborn Errors of Metabolism, 763
Anne L. Matthews and Nathaniel H. Robin

28. Neonatal Surgery, 786

Brian T. Bucher, Annette S. Pacetti, Harold N. Lovvorn III, and
Brian S. Carter

UNIT SIX

Psychosocial Aspects of Neonatal
Care
29. Families in Crisis: Theoretical and Practical
Considerations, 821

Sandra L. Gardner, Kristin Voos, and Patti Hills

30. Grief and Perinatal Loss, 865
Sandra L. Gardner and Brian S. Carter

31. Discharge Planning and Follow-Up of the

Neonatal Intensive Care Unit Infant, 903
Angel Carter, Linda Gratny, and Brian S. Carter

32. Ethics, Values, and Palliative Care in Neonatal
Intensive Care, 924

Julie R. Swaney, Nancy English, and Brian S. Carter


UNIT ONE

1


EVIDENCE-BASEDPRACTICE

EVID EN C E- BASED
C LIN IC AL PR AC T IC E
ALFONSOF. PANTOJAANDMARYENZMANHINES

G

lobally, health care systems are experiencing
challenges when evaluating therapies, quality of care, and the risk of adverse events
in clinical practice. O ten health care systems ail
to optimally use evidence. This failure is either
from underuse, overuse, or misuse of evidence-based
therapies and/ or system failures.75 Evidence-based
practice (EBP) requires the integration o the best
research evidence with our clinical expertise and
each patient’s unique values and circumstances. 75
EBP approaches in all fields of health care could prevent therapeutic disasters resulting from the informal
“let’s-try-it-and-see” methods of testing new therapies that are not recognized as risky. The epidemic
of retinopathy attributable to the indiscriminate use
of supplemental oxygen; gray baby syndrome attributable to the administration of chloramphenicol;
kernicterus attributable to the introduction of sulfonamides65; and death due to liver toxicity of 40
premature newborns attributable to the administration of a parenteral form of vitamin E (E-Ferol)71
are examples of these therapeutic misadventures in
the field of neonatal care. Silverman described how
painfully slow health care providers were to embrace
a culture of skepticism and emphasizes, “We must
insist on the highest standards of evidence in studies involving the youngest human beings; and, since
there is no short route to this goal, we must prepare
to be patient.”64 The use of experimentation and the

scientific method has ultimately led to our present
views of how to ask and answer clinical questions.56
Mistakes have also occurred at the other
extreme, as well, resulting in a ailure to adopt

therapies that are o proven benef t or an assumption that the risks associated with changing
practice justi y complacency about current treatments. The significant delay in the adoption of antenatal corticosteroids by the obstetric community to
promote fetal lung maturation19,68 is a good example
of failure to use the available evidence. O ne o the
most important benef ts o EBP is the constant
questioning: “Have our current clinical practices
been studied in appropriately selected populations, o su f cient size to accurately predict their
e f cacy, benef t, sa ety, side e ects, and cost?”
EBP is a systematic way to integrate the best
patient-centered, clinically relevant research
with our clinical expertise and with the unique
pre erences, concerns, and expectations that
each patient brings to a clinical encounter. 75 Furthermore, EBP presents an opportunity to enhance
patient health and illness outcomes, increase staff satisfaction, and reduce health care expenses. There is
great interest in identi ying barriers and acilitators that could help in closing the knowledgeto-practice gap that is inherent to the acceptance
and adoption o EBP by all providers. 76

FINDING HIGH-QUALITY
EVID ENCE
As new therapies are integrated into neonatal care,
health care providers must continue to increase
existing knowledge of the health and health problems of newborns. Providers need to ormulate

PUR PLE type highlights content that is particularly applicable to clinical settings.


1


2

UNIT ONE Evidence-Based Practice

well-designed questions about the specif c clinical encounter and learn how to evaluate the
quality o evidence regarding risks and benef ts
o new practices. Most clinical questions arise
through daily practice and often involve knowledge gaps in background (general knowledge) and
foreground (specific knowledge to inform clinical
decisions or actions).The knowledge needs will vary
according to the experience of the clinician.75
It is not the purpose of this chapter to provide
a detailed review of the various research designs
that permit reliable scientific inference. R ather, our
purpose is to promote the propositions that (1)
challenge clinical observations and wisdom by
f nding the current best evidence and (2) care ul
assessment and critique o research that supports
or challenges the use o new and established
clinical practices.
Clinical observations, although valuable in
shaping research questions, are limited by selective perception—a desire to see a strategy work
or ail to work. At times, a single case or case study
may prompt us to question whether we should consider changing current practice. In some situations,
much can be learned from carefully maintained
databases. Such knowledge is gained only when we
have formed databases with clear intentions and

have collected the necessary data.
Sinclair and Bracken67 described our levels o
clinical research used to evaluate sa ety and e f cacy o therapies, based on their ability to provide
an unbiased answer. In ascending order, these are
(1) single case or case series reports without controls, (2) nonrandomized studies with historical
controls, (3) nonrandomized studies with concurrent controls, and (4) randomized controlled
trials (R CTs). R CTs test hypotheses by using
randomly assigned treatment and control groups
o adequate size to examine the e f cacy and
sa ety o a new therapy. In theory, random assignment of the treatment balances unknown or unmeasured factors that might otherwise bias the outcome
of the trial. A meta-analysis is a systematic review
o the current literature that uses statistical methods to combine the results o individual studies and summarizes the results (http:/ / neonatal.
cochrane.org).18 Tyson79 has suggested criteria
for identifying proven therapies in current literature (Box 1-1). Ideally, therapeutic recommendations are supported by evidence rom systematic
reviews o R CTs; however, such evidence is

BOX

1-1

PROVENTHERAPIES

Reported to be benefcial in a well-per ormed meta-analysis o all trials
or
Benefcial in at least one multicenter trial or two single-center trials
Modifed romTyson JE: Use o unproven therapies in clinical practice and research: how
can we better serve our patients and their amilies? Semin Perinatol 19:98, 1995.

T AB L E


1-1

LEVELSOFEVIDENCE

LEVELOFEVIDENCE

THERAPY/ PREVENTION/ ETIOLOGY/ HARM

1a

Systematic reviews o RCTs

1b

Individual RCTwith narrowconfdence interval

1c

All or none

2a

Systematic reviewo cohort studies

2b

Individual cohort study (including low-quality
RCT[less than 80% ollow-up])

3a


Systematic reviewo case-control study

3b

Individual case-control study

4

Case-controlled studies

5

Expert opinion without critical appraisal

From Straus SE, Richardson WS, Haynes RB: Evidence-based medicine: how to practice
and teach it, ed 4, London, 2011, Harcourt.
RCT, Randomized controlled trial.

not always available. It is then important to have
a system to grade the strength of the quality of the
evidence found. An international collaboration
has developed GR ADE, providing an explicit
strategy or grading evidence and the strength o
recommendations. 36 GR ADE classif es the evidence into one o our levels: high, moderate,
low, and very low (Table 1-1). The strength of the
recommendation is graded as strong or weak. Factors
that influence the strength of the recommendation
include desirable or undesirable effects, values, preferences, and economic implications (Figure 1-1).
Although conclusions drawn from quantitative

studies (R CTs, meta-analysis of R CTs) are regarded
as the strongest level of evidence, evidence from
descriptive and qualitative studies should be factored


CHAPTER 1 Evidence-Based Clinical Practice

ce

Me ta a na lys is
S ys te ma tic
re vie ws

Q

u

a

lit
y

o

f

e

vi
d


e

n

TRIP da ta ba s e
s e a rche s the s e
s imulta ne ous ly

Critica lly a ppra is e d
topics
(e vide nce s ynthe s e s )

3

Filte re d
informa tion

Critica lly a ppra is e d individua l
a rticle s (a rticle s ynops e s )
Ra ndomize d controlle d tria ls (RCTs )
Cohort s tudie s

Unfilte re d
informa tion

Ca s e -controlle d s tudie s
Ca s e s e rie s /Re ports
Ba ckground informa tion/Expe rt opinion


FIGURE 1-1 Evidence appraisal. (Adapted romDiCenso A, Bayley L, Haynes RB: Accessing pre-appraised evidence: fne-tuning the 5S
model into the 6S model, Evid Based Nurs 12:99, 2009.)

into clinical decisions. Q ualitative research provides guidance in deciding whether the f ndings
o quantitative studies could be replicated in
various patient populations. Q ualitative research
can also acilitate an understanding o the experience and values o patients. The validity, importance, and applicability of qualitative studies need to
be evaluated in a similar way as quantitative studies.

PRESSURES TO INTERVENE
R CTs o appropriate size are cited as providing
the best evidence or guiding clinical decisions;
however, many take years to complete and publish. Providers f nd it di f cult to delay introduction
o promising therapies. Bryce and Enkin12 discussed
myths about R CTs and rationales for not conducting
them. O ne myth is that randomization is unethical.
This might be true in rare instances when an intervention is dramatically effective and lifesaving. The
more common situation is one where there is limited
evidence for a current or alternative strategy.
Pressure to intervene is, however, often overpowering. Believing that an infant is in trouble, interventions occur through a cascade of interventions,49 one

leading to the next and each carrying risk. One of
the most frequently cited examples is the epidemic
of blindness associated with the unrestricted use of
oxygen in newborns.63,64 Oxygen, used since the
early 1900s for resuscitation and treatment of cyanotic episodes, was noted in the 1940s to “correct”
periodic breathing in premature infants. After World
War II and introduction of new gas-tight incubators,
an epidemic of blindness occurred, resulting from
retrolental fibroplasia (R LF). Silverman63 pointed

out that although many causes were suspected, it
was not until 1954 that a multicenter, controlled trial
confirmed the association between high oxygen concentrations and R LF. Frequently forgotten, however,
is that in subsequent years, mortality was increased in
infants cared for with an equally experimental regimen of strict restriction of oxygen administration
and many survivors had spastic diplegia. In the 1960s,
the introduction of micro techniques for measuring
arterial oxygen tension permitted better monitoring of oxygen therapy, with a reduction in mortality,
spastic diplegia, and R LF, now called retinopathy of
prematurity (ROP). Severe ROP is currently limited
to extremely low-birth-weight (ELBW) infants.63
R esearch continues to explore causes, preventive
measures, and treatments (see Chapter 31).


4

UNIT ONE Evidence-Based Practice

Large multinational, pragmatic R CTs to
resolve the uncertainty surrounding the most
appropriate levels o oxygen saturation in premature in ants have been recently conducted
and the results published. 60,77,78 The publication of
the results of the SUPPORT trial77 brought about a
significant debate about the ethical aspects of comparative effectiveness research and parental informed
consent when one of the elements of the composite
outcome was death before discharge.63 The practice
of allowing very-low-birth-weight (VLBW) infants
to maintain lower O 2 saturations during the first
weeks of life had been widely disseminated throughout the United States and the world due to anecdotal

reports of a significant decrease in the severity of
ROP and blindness with this approach.17 The SUPPO R T 77 and BO O ST II78 trials showed a signif cant decrease in the requency o severe R O P
and an increase in mortality rate in the low-saturation group. However, another study with a
similar design60 showed no signif cant e ect on
the rate o death or disability at 18 months.
The desire to see an intervention “work”
encourages practitioners and investigators to seek
early signs o benef t. Long-term e ects are requently overlooked. One reason is that they may
not be foreseen. Consider the example of diethylstilbestrol (DES). DES administration to pregnant
women was introduced in 1947 without clinical trials to prevent miscarriage, fetal death, and preterm
delivery.12,30 It was thought to be effective after
uncontrolled studies despite controlled trials summarized in an overview (meta-analysis) by Goldstein
et al34 (Table 1-2) that showed the opposite. Clearly,
DES was not effective, but it continued to be used
until the 1970s, when the Food and Drug Administration (FDA) finally disapproved its use. The unforeseen result was that female children born to mothers
who were given DES had structural abnormalities of
the genital tract, pregnancy complications, decreased
fertility, and an increased risk for vaginal adenocarcinoma in young women. Male children had epididymal cysts. This is not the only example of physicians
continuing to use therapies that have been shown in
R CTs to be of no benefit.15
The costs of long-term studies and follow-up
surveillance are numerous. However, when effects
are measured later in life (e.g., psychological problems, ability to function in school), the cost cannot
determine study design. Even when randomized trials are conclusive, unanswered questions remain:Will

T AB L E

1-2

EFFECTSOFDIETHYLSTILBESTROL(DES)

ONPREGNANCYOUTCOMES
TYPICALODDS
RATIO*

95%CONFIDENCE
LIMITS

Miscarriage

1.20

0.89-1.62

Stillbirth

0.95

0.50-1.83

Neonatal death

1.31

0.74-2.34

All three

1.38

0.99-1.92


Prematurity

1.47

1.08-2.00

Data romGoldstein PA, Sacks HS, Chalmers TC: Hormone administration or the maintenance o pregnancy. In Chalmers I, Enkin M, Keirse M, editors: Effective care in pregnancy
and childbirth, NewYork, 1989, Ox ord University Press.
*An odds ratio is an estimate o the likelihood (or odds) o being a ected byan exposure
(e.g., a drug or treatment), compared with the odds o having that outcome without having been exposed. Women receiving DES did not have ewer stillbirths, premature births,
or miscarriages than women who were untreated.

a technology or treatment have the same effect in
all settings? Has an “appropriate” target population
been selected? Are there long-term unforeseeable
consequences?

EVALUATION OF THERAPIES
The major cause of death in premature infants is
respiratory failure from respiratory distress syndrome
(R DS) (see Chapter 23). Previously called hyaline
membrane disease, this syndrome of expiratory grunting, nasal flaring, chest wall retractions, and cyanosis
unresponsive to high oxygen concentrations was a
mystery until the 1950s.64
The evaluation of various therapies for R DS
contrasts the value of controlled and uncontrolled
trials. Sinclair66 noted that uncontrolled studies were
more likely to show benefit than controlled trials.
In 19 uncontrolled studies, 17 popular therapies

showed “benefit.” In 18 controlled studies, only 9
demonstrated benefit. An untrained reviewer of the
research might base clinical practice on faulty conclusions of uncontrolled trials.

Surfactant Therapy
In contrast to many proposed treatments, suractant therapy in premature in ants has been


CHAPTER 1 Evidence-Based Clinical Practice

well studied in R CTs. 3,37 Studies have evaluated
the use of surfactant in treatment of R DS, including the optimal source and composition of surfactant
and prophylactic versus rescue treatment. Morbidity
(including pneumothorax, periventricular or intraventricular hemorrhage, bronchopulmonary dysplasia [BPD], and patent ductus arteriosus) and mortality
rates in treatment and control groups have been
compared. Systematic reviews of surfactant therapy
confirm the effect of surfactant therapy in reducing
the risk of morbidity and mortality.67,72 Although
R CTs involving thousands o newborns have
clearly demonstrated the benef ts o sur actant
therapy, unanswered questions remain. One of

these questions is if prophylactic administration of
surfactant to an infant judged to be at risk of developing R DS was better than early selective use of surfactant to infants with established R DS. Early trials
demonstrated a decreased risk of air leak and mortality with the prophylactic approach. However, recent
R CTs that reflect current practice (i.e., greater utilization of maternal steroids and routine postdelivery
stabilization on continuous positive airway pressure
[CPAP]) do not support these differences and actually demonstrate less risk of chronic lung disease or
death when using early stabilization on CPAP with
selective surfactant administration to infants requiring intubation59,77 (Figure 1-2).


Re vie w: P rophyla ctic ve rs us s e le ctive us e of s urfa cta nt in pre ve nting morbidity a nd morta lity in pre te rm infa nts
Compa ris on: 2 P rophyla ctic s urfa cta nt vs . tre a tme nt of e s ta blis he d re s pira tory dis tre s s in pre te rm infa nts le s s tha n 30 we e ks ge s ta tion
Outcome : 1 Ne ona ta l morta lity

S tudy or s ubgroup

P rophyla ctic
n/N

S e le ctive
n/N

Ris k Ra tio
M-H, Fixe d, 95% CI

We ight

Ris k Ra tio
M-H, Fixe d, 95% CI

1 S tudie s without routine a pplica tion of CP AP
Be vila cqua 1996

28/136

46/132

17.6%


0.59 [ 0.39, 0.89 ]

Be vila cqua 1997

9/49

9/44

3.6%

0.90 [ 0.39, 2.06 ]

Dunn 1991

9/62

8/60

3.1%

1.09 [ 0.45, 2.63 ]

Egbe rts 1993

8/75

14/72

5.4%


0.55 [ 0.24, 1.23 ]

Ke ndig 1991

23/235

40/244

14.8%

0.60 [ 0.37, 0.97 ]

Me rritt 1991

27/76

21/72

8.2%

1.22 [ 0.76, 1.95 ]

Wa lti 1995

15/134

23/122

9.1%


0.59 [ 0.33, 1.08 ]

S ubto tal (95% CI)

767

746

61.8%

0.71 [ 0.58, 0.88 ]

Tota l e ve nts : 119 (P rophyla ctic), 161 (S e le ctive )
He te roge ne ity: Chi?? 8.27, df 6 (P 0.22); I??
Te s t for ove ra ll e ffe ct: Z 3.11 (P
0.0019)

27%

2 S tudie s with routine a pplica tion of CP AP
Dunn 2011

10/209

8/221

2.9%

1.32 [ 0.53, 3.28 ]


S upport 2010

114/653

94/663

35.3%

1.23 [ 0.96, 1.58 ]

S ubto tal (95% CI)

862

884

38.2%

1.24 [ 0.97, 1.58 ]

100.0%

0.91 [ 0.78, 1.07 ]

Tota l e ve nts : 124 (P rophyla ctic), 102 (S e le ctive )
He te roge ne ity: Chi?? 0.02, df 1 (P 0.88); I??
Te s t for ove ra ll e ffe ct: Z 1.73 (P
0.083)

To tal (95% CI)


1629

0.0%

1630

Tota l e ve nts : 243 (P rophyla ctic), 263 (S e le ctive )
He te roge ne ity: Chi?? 18.64, df 8 (P
0.02); I?? 57%
Te s t for ove ra ll e ffe ct: Z 1.11 (P
0.27)
Te s t for s ubgroup diffe re nce : Chi?? 11.24, df 1 (P
0.00); I??

0.2
Fa vors prophyla ctic

5

91%

0.5

1

2

5


Fa vors s e le ctive

FIGURE 1-2 Table showing e ect o prophylactic versus selective sur actant administration on morbidity and mortality rates in preterm
in ants. (FromRojas-Reyes X, MorleyC, Soll R: Prophylacticversus selective use o sur actant in preventing morbidityandmortalityin preterm
in ants, Cochrane Database Syst Rev3:CD000510, 2012.)


6

UNIT ONE Evidence-Based Practice

Corticosteroid Therapy
Misuse o corticosteroids in perinatal medicine
illustrates the consequences o ailure to practice
evidence-based medicine. Many practitioners initially declined to use antenatal steroids to promote
maturation of the immature fetal lung and prevent
R DS despite strong supportive evidence, demonstrating a failure to use a proven therapy.
ANTENATAL CORTICOSTEROID
THERAPY: SINGLE COURSE

Antenatal administration of corticosteroids to pregnant women who threatened to deliver prematurely
was first shown in 1972 to decrease neonatal mortality rate and the incidence of R DS and intraventricular hemorrhage (IVH) in premature infants.44 In
1990, Crowley et al21 used meta-analysis to evaluate
12 R CTs of maternal corticosteroid administration
involving more than 3000 women. The data showed
that maternal corticosteroid treatment significantly
reduced the risk for neonatal mortality, R DS, and
IVH. Sinclair,68 using a “cumulative meta-analysis”
approach of randomized trials, clearly demonstrated
that the aggregate evidence that was sufficient to

show that this treatment reduces the incidence of
R DS and neonatal death was available for almost 20
years before the use of antenatal corticosteroids was
widely accepted by the medical community.
This led to the National Institutes of Health
(NIH) consensus development conference statement
on “Effects of Corticosteroids for Fetal Maturation
on Perinatal O utcomes.” 50 Antenatal corticosteroid
treatment of women at risk for preterm delivery
between 24 and 34 weeks of gestation has been
shown to be effective and safe in enhancing fetal
lung maturity and reducing neonatal mortality. Yet
adoption by caretakers was inexplicably slow.42
ANTENATAL CORTICOSTEROID
THERAPY: REPEATED COURSES

At the same time, other practitioners administered
repeated doses despite lack o evidence o additional benef t and questions about sa ety, representing unproven use o a proven therapy.
R epeated courses of antenatal corticosteroids have
been shown in humans and animals to improve lung
function and the quantity of pulmonary surfactant.22,35 They may also have adverse effects on lung
structure, fetal somatic growth, and neonatal adrenocortical function, as well as poorly understood

effects on blood pressure, carbohydrate homeostasis,
and psychomotor development.22,48 A 2000 NIH
Consensus Development Conference found limited
high-quality studies on the use of repeated courses
of antenatal steroids.51 The consensus statement
discouraged routine use o repeated courses o
antenatal corticosteroids. Published preliminary

reports of infants exposed to multiple doses of antenatal steroids reaching school age are emerging.6 A
recent meta-analysis of infants exposed to more than
one course of antenatal corticosteroids concluded
that “although the short-term neonatal benefits of
repeated courses of antenatal corticosteroids support
their use, long-term benefits have not been demonstrated and long-term adverse effects have not been
ruled out. The adverse effect of repeated doses of
antenatal corticosteroids on birth weight and weight
at early childhood follow-up is a concern. Caution
should therefore be exercised to ensure that only
those women who are at particularly high risk of
very early preterm birth are offered treatment with
repeated courses of antenatal corticosteroids.” 23 The
American College o O bstetricians and Gynecologists (ACO G) recommends a repeat course
o antenatal steroids i the etus is less than 34
weeks o gestation and the previous course o
antenatal steroids was administered more than
14 days earlier. 4
POSTNATAL STEROID THERAPY

Postnatal glucocorticoids, administered to the
in ant a ter birth, have been widely used despite
weak evidence o long-term benef t and suggestions o possible harm, illustrating use o an
uncertain therapy.42 Despite early calls for caution
in the use of postnatal corticosteroids to decrease
the risk for chronic lung disease and limit ventilator time, they were used liberally in the 1990s.70,74 A
number o years passed be ore R CTs o postnatal
corticosteroid administration included long-term
ollow-up. Taken together, these studies showed
positive short-term effects on the lungs. Studies also

showed increased blood pressure and blood glucose
concentrations in the short term; increased incidence
of septicemia and gastrointestinal perforation in the
intermediate term; and with dexamethasone administered soon after birth, abnormal neurodevelopmental outcome, including cerebral palsy, in the long
term.25,37,43,74 An increased risk for septicemia should
have been anticipated, because it was first identified
in an R CT by R eese et al58 over 50 years earlier.


CHAPTER 1 Evidence-Based Clinical Practice

In 2002, the American Academy of Pediatrics (Committee on Fetus and Newborn) and the
Canadian Paediatric Society (Fetus and Newborn
Committee) advised against the use of systemic
dexamethasone and suggested that “outside the context of a R CT that include assessment of long-term
development, the use of corticosteroids should be
limited to exceptional clinical circumstances (e.g.,
an infant on maximal ventilator support and oxygen requirement).” 2 A 2005 reanalysis of many of
the same data by Doyle et al25 suggests that relative
risks and benefits of postnatal corticosteroids vary
with level of risk for BPD. When the risk for BPD
or death is high, the risk for developmental impairment from postnatal corticosteroids might be outweighed by benefit.27,29 Watterberg et al83 suggested
that hydrocortisone might have the benefits of dexamethasone on the lungs without adverse neurologic
effects. Following these statements, the exposure of
at-risk prematures decreased dramatically.81,82

QUALITATIVE RESEARCH
EVALUATING EXPERIENCES IN
THE NEONATAL INTENSIVE
CARE UNIT

The contribution o qualitative research to EBP is
evident when “best evidence rom R CTs” may
or may not work within the context o specif c
neonatal intensive care unit (NICU) environments. The context can be quite variable and influenced by practitioners and staff, the unit leadership,
and family influence within the unit. The implementation o amily-centered care in the NICU
has shown promising outcomes, including minimizing parental stress related to the technology and complex care o a tiny, ragile preterm
in ant. 46 An environment o amily- centered
care has also contributed in a positive way to
the success o the implementation o clinical
practice guidelines and evaluating outcomes. 26
Q ualitative studies are useful when limited information exists about a phenomenon or a deficiency is
evident in the quality, depth, or detail of research
in a specific area of clinical practice. Q ualitative
research contributes to EBP in several areas:
(1) descriptions o patient needs and experiences;
(2) providing the groundwork or instrument
development and evaluation; and (3) elaborating
on concepts relative to theory development. 47

7

Systematic reviews and meta-analyses are emerging in qualitative literature researching parental
experiences in the NICU. 33,52 In neonatology,
qualitative studies provide in-depth views of parental
and provider experiences within the NICU setting
to humanize the health care of fragile infants. Parents o in ants who require NICU care begin an
experience o parenthood in an un amiliar and
intimidating environment that results in delayed
attachment 38,62; high levels o stress, including
anxiety, depression, trauma symptoms, and isolation (both physical and emotional) rom their

in ant 13,31; lack o disclosure o their in ant’s
condition; and a lack o control. 16 Mothers often
experience feelings of ambivalence, shame, guilt, and
failure that the infant is in the NICU.61 Parents also
experience the tension between exclusion and participation in their infant’s care.84 In contrast, parents describe actors that contribute to parental
satis action in the NICU, including assurance,
caring communication, provision o consistent
in ormation, education, 20 environmental ollowup care, appropriate pain management, 31 parental participation in care, and emotional, physical,
and spiritual support. 20 Conversely, health care
professionals’ experiences of parental presence and
participation in the NICU revealed similar findings
to those described by parents: the need to develop
a caring environment for parents to be present and
take care of their child by guiding parents and giving
parents’ permission to care for their child, a need for
personnel training in the art of dealing with parents
in crisis, identifying a balance between closeness and
distance, and dealing with parental worry.85,86
Quality care is a major issue currently evaluating
the delivery of health care services, yet little research
has been conducted on what parents of premature
infants perceive as quality nursing care. Price57 used
a qualitative approach to reveal the meaning o
quality nursing care rom parents’ perspectives
and identif ed concepts inherent in the process
o receiving quality nursing care. Four stages
were identif ed: (1) maneuvering, (2) a process
o knowing, (3) building relationships, and (4)
quality care. For parents, nontechnical aspects
o care, such as com orting in ants a ter pain ul

procedures, were as important as the technical
aspects o care. Another qualitative study revealed
seven categories that influence changes in practice:
(1) staffing issues, (2) consistency in practice, (3) the
approval process for change, (4) a multidisciplinary